Pulm Med. 2021 Jun 18;2021:5488591. doi: 10.1155/2021/5488591. eCollection 2021.

ABSTRACT

The S100 protein family consists of over 20 members in humans that are involved in many intracellular and extracellular processes, including proliferation, differentiation, apoptosis, Ca2 + homeostasis, energy metabolism, inflammation, tissue repair, and migration/invasion. Although there are structural similarities between each member, they are not functionally interchangeable. The S100 proteins function both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated responses of multiple members of the S100 family are observed in several diseases, including the lungs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and lung cancer). To this degree, extensive research was undertaken to identify their roles in pulmonary disease pathogenesis and the identification of inhibitors for several S100 family members that have progressed to clinical trials in patients for nonpulmonary conditions. This review outlines the potential role of each S100 protein in pulmonary diseases, details the possible mechanisms observed in diseases, and outlines potential therapeutic strategies for treatment.

PMID:34239729 | PMC:PMC8214497 | DOI:10.1155/2021/5488591

Front Immunol. 2021 Jun 22;12:695954. doi: 10.3389/fimmu.2021.695954. eCollection 2021.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus which colonizes the airways of patients with asthma and cystic fibrosis. Its diagnosis could be difficult in some cases due to atypical presentations especially when there is no medical history of asthma. Treatment of ABPA is frequently associated to side effects but cumulated drug toxicity due to different molecules is rarely reported. An accurate choice among the different available molecules and effective on ABPA is crucial. We report a case of ABPA in a woman without a known history of asthma. She presented an acute bronchitis with wheezing dyspnea leading to an acute respiratory failure. She was hospitalized in the intensive care unit. The bronchoscopy revealed a complete obstruction of the left primary bronchus by a sticky greenish material. The culture of this material isolated Aspergillus fumigatus and that of bronchial aspiration fluid isolated Pseudomonas aeruginosa. The diagnosis of ABPA was based on elevated eosinophil count, the presence of specific IgE and IgG against Aspergillus fumigatus and left segmental collapse on chest computed tomography. The patient received an inhaled treatment for her asthma and a high dose of oral corticosteroids for ABPA. Her symptoms improved but during the decrease of corticosteroids, the patient presented a relapse. She received itraconazole in addition to corticosteroids. Four months later, she presented a drug-induced hepatitis due to itraconazole which was immediately stopped. During the monitoring of her asthma which was partially controlled, the patient presented an aseptic osteonecrosis of both femoral heads that required surgery. Nine months after itraconazole discontinuation, she presented a second relapse of her ABPA. She received voriconazole for nine months associated with a low dose of systemic corticosteroid therapy with an improvement of her symptoms. After discontinuation of antifungal treatment, there was no relapse for one year follow-up.

PMID:34239516 | PMC:PMC8259593 | DOI:10.3389/fimmu.2021.695954

Nat Med. 2021 Jul 8. doi: 10.1038/s41591-021-01403-9. Online ahead of print.

ABSTRACT

An 81-year-old immunocompetent patient with bronchiectasis and refractory Mycobacterium abscessus lung disease was treated for 6 months with a three-phage cocktail active against the strain. In this case study of phage to lower infectious burden, intravenous administration was safe and reduced the M. abscessus sputum load tenfold within one month. However, after two months, M. abscessus counts increased as the patient mounted a robust IgM- and IgG-mediated neutralizing antibody response to the phages, which was associated with limited therapeutic efficacy.

PMID:34239133 | DOI:10.1038/s41591-021-01403-9

Nat Biomed Eng. 2021 Jul 8. doi: 10.1038/s41551-021-00757-2. Online ahead of print.

ABSTRACT

Creating in vitro models of diseases of the pancreatic ductal compartment requires a comprehensive understanding of the developmental trajectories of pancreas-specific cell types. Here we report the single-cell characterization of the differentiation of pancreatic duct-like organoids (PDLOs) from human induced pluripotent stem cells (hiPSCs) on a microwell chip that facilitates the uniform aggregation and chemical induction of hiPSC-derived pancreatic progenitors. Using time-resolved single-cell transcriptional profiling and immunofluorescence imaging of the forming PDLOs, we identified differentiation routes from pancreatic progenitors through ductal intermediates to two types of mature duct-like cells and a few non-ductal cell types. PDLO subpopulations expressed either mucins or the cystic fibrosis transmembrane conductance regulator, and resembled human adult duct cells. We also used the chip to uncover ductal markers relevant to pancreatic carcinogenesis, and to establish PDLO co-cultures with stellate cells, which allowed for the study of epithelial-mesenchymal signalling. The PDLO microsystem could be used to establish patient-specific pancreatic duct models.

PMID:34239116 | DOI:10.1038/s41551-021-00757-2

Int J Clin Pract. 2021 Jul 8:e14616. doi: 10.1111/ijcp.14616. Online ahead of print.

ABSTRACT

AIMS: Patients with cystic fibrosis (CF) develop with progressive loss of lung function and aerobic fitness. However, the precise mechanisms of exercise intolerance are still controversial and appear to be influenced by several factors. This study aimed to evaluate the association of aerobic fitness with free DNA levels in the sputum of patients with CF.

METHODS: This cross-sectional study included patients with CF older than 6 years, free from active exacerbations, but who were able to produce spontaneously expectorated sputum. Extracellular DNA in the sputum was quantified. Lung function (spirometry) and aerobic fitness (cardiopulmonary exercise testing - CPET) were performed. In addition, demographic, anthropometric and clinical data were collected.

RESULTS: Sixteen patients with a mean age of 19.4±6.9 years and mean forced expiratory volume in the first second (FEV1 ) of 51.8±28.1 (% of predicted) were included. Mean peak oxygen consumption (VO2 peak) was 32.8±5.2 mL.kg-1 .min-1 , oxygen saturation at the end of the test was 90.6±6.3% and mean extracellular DNA levels was 305.3±153.6 μg/mL. Individuals with a VO2 peak ≤ 30 mL.kg-1 .min-1 (P=.03) and a SpO2 ≤ 90% at the end of the test (P=.03) had a greater amount of extracellular DNA in the sputum. The proportion of patients with reduced VO2 peak in the group of patients with the lowest concentration of DNA in the sputum (<243 μg/mL) was significantly lower (0% vs. 100%; P=.04).

CONCLUSION: There is an association between the presence of free DNA in sputum and aerobic fitness in patients with CF.

PMID:34235820 | DOI:10.1111/ijcp.14616

J Asthma Allergy. 2021 Jul 1;14:755-771. doi: 10.2147/JAA.S291774. eCollection 2021.

ABSTRACT

RATIONALE: The National Heart, Lung, and Blood Institute (NHLBI) recommend a stepwise approach to asthma management, with the goals of maintaining asthma control and reducing exacerbations. Although asthma treatments reduce the frequency of exacerbations, they still occur. We aimed to characterize the treated United States of America (US) adult asthma population, including those experiencing exacerbations, in terms of socio-demographics, clinical characteristics, and healthcare resource utilization (HRU).

PATIENTS AND METHODS: A retrospective cohort of asthma patients aged ≥18 years on 01 January 2014 with ≥1 ICD-9 asthma code (493.xx) enrolled in a US healthcare claims database during 2013-2014. Patients who had ≥2 asthma medication dispensings during 2013 (baseline), including ≥1 in the 90-day period before index date, were classified according to NHLBI step. Patients with chronic obstructive pulmonary disease, cystic fibrosis, or lung cancer diagnoses were excluded. Demographics, comorbidities, clinical characteristics, and HRU were described during baseline. Exacerbations and HRU were described during 2014 (follow-up period).

RESULTS: In total, 72,156 patients were included; 10,590 (14.7%) had ≥1 exacerbation during follow-up. Approximately 44% of patients were classified as NHLBI Steps 1-2, 41% as Steps 3-4, and 11% as Steps 5-6. Exacerbation frequency increased with step (Steps 1, 2, and 3: 12-14%; Steps 4, 5, and 6: 16-26%). Compared with the overall population during baseline, patients with an exacerbation had similar demographics, but differences were observed for comorbid allergic rhinitis (46.4% vs 40.1%, respectively), blood eosinophil counts ≥300 cells/μL (45.5% vs 39.6%, respectively), and asthma-related healthcare encounters (62.9% vs 52.4%, respectively). Overall, asthma-related HRU during follow-up increased with NHLBI step.

CONCLUSION: Exacerbations were observed among patients classified at each NHLBI step and were more frequent with increasing step. Exacerbations and asthma-related HRU highlight the continued unmet need in the treated US asthma population.

PMID:34234471 | PMC:PMC8257074 | DOI:10.2147/JAA.S291774

Am J Physiol Lung Cell Mol Physiol. 2021 Jul 1;321(1):L287-L289. doi: 10.1152/ajplung.00246.2021.

NO ABSTRACT

PMID:34233142 | DOI:10.1152/ajplung.00246.2021

Pediatr Pulmonol. 2021 Jul 7. doi: 10.1002/ppul.25563. Online ahead of print.

ABSTRACT

INTRODUCTION: To help open the clinician dialogue regarding cannabis use in persons with CF in the U.S., we aimed to describe current practices of use assessment and documentation processes related to cannabis.

METHODS: A cross sectional, anonymous survey study was distributed via email to CF directors and coordinators and to the Cystic Fibrosis Foundation (CFF) listservs of nurse, pharmacist, dietitian, social worker and psychology care team members. The survey tool included multiple choice, scaled and open ended items, which assessed participants' awareness of current cannabis laws in their state, prescribing practices for medical marijuana, screening and documentation practices, knowledge of and what indications participants believe cannabis and cannabidiol (CBD) could be beneficial. Data was analyzed using descriptive statistics.

RESULTS: There were 282 survey participants, with majority as providers (28%) and social workers (29%), representing all U.S. regions. Participants varied in terms of frequency of evaluating cannabis use, with 15.4% "always," 48.4% "sometimes," and 41% "rarely" or "never" asking about it. Regarding recreational versus medical cannabis use, 55.4% and 62.5% reported documentation of each type in the medical record, respectively. Participants reported appetite, pain, and nausea as the top three advocated indications for use. About 35% and 72% of participants felt "slightly" or "not at all" prepared to answer patient/family questions about cannabis and CBD, respectively.

CONCLUSIONS: The approach to cannabis use assessment, documentation, and education across CF care centers is variable. There is a need for care team and patient/caregiver education materials about cannabis/CBD and CF. This article is protected by copyright. All rights reserved.

PMID:34232573 | DOI:10.1002/ppul.25563

JMIR Pediatr Parent. 2021 Jul 7. doi: 10.2196/25014. Online ahead of print.

ABSTRACT

BACKGROUND: For individuals with cystic fibrosis (CF), adolescence and young adulthood are times of significant vulnerability and have been associated with clinical and psychosocial challenges. Social media may offer innovative care delivery solutions to address these challenges.

OBJECTIVE: The current study explored motivations and attitudes on current social media use, as well as preferences for a social media platform in a sample of adolescents and young adults with CF.

METHODS: A cross-sectional survey was administered to 50 adolescents and young adults with CF followed at a large pediatric-adult CF Center. The survey included questions regarding social media platform utilization, attitudes towards general and CF specific online activities, and preferences for a CF specific care delivery platform.

RESULTS: YouTube (86%), Snapchat (78%) and Instagram (76%) were the most commonly used social media platforms. Adolescents and young adults with CF do not report routinely utilizing social media for health-related information acquisition, social support or to help with adherence. However, their perceptions of social media utilization and preferences for platform development suggest interest in doing so in the future.

CONCLUSIONS: Adolescents and young adults with CF utilize social media and express interest in the development of a social media platform. Platform development will allow for gaps in healthcare delivery to be addressed by improving social support and adherence while augmenting current methods of health information acquisition.

PMID:34232121 | DOI:10.2196/25014

Microb Genom. 2021 Jul;7(7). doi: 10.1099/mgen.0.000582.

ABSTRACT

Achromobacter spp. are emerging pathogens in patients with cystic fibrosis (CF) and Achromobacter spp. caused infections are associated with more severe disease outcomes and high intrinsic antibiotic resistance. While conventional CF pathogens are studied extensively, little is known about the genetic determinants leading to antibiotic resistance and the genetic adaptation in Achromobacter spp. infections. Here, we analysed 101 Achromobacter spp. genomes from 51 patients with CF isolated during the course of up to 20 years of infection to identify within-host adaptation, mutational signatures and genetic variation associated with increased antibiotic resistance. We found that the same regulatory and inorganic ion transport genes were frequently mutated in persisting clone types within and between Achromobacter species, indicating convergent genetic adaptation. Genome-wide association study of six antibiotic resistance phenotypes revealed the enrichment of associated genes involved in inorganic ion transport, transcription gene enrichment in β-lactams, and energy production and translation gene enrichment in the trimethoprim/sulfonamide group. Overall, we provide insights into the pathogenomics of Achromobacter spp. infections in patients with CF airways. Since emerging pathogens are increasingly recognized as an important healthcare issue, our findings on evolution of antibiotic resistance and genetic adaptation can facilitate better understanding of disease progression and how mutational changes have implications for patients with CF.

PMID:34232117 | DOI:10.1099/mgen.0.000582

Microbiol Spectr. 2021 Jul 7:e0002921. doi: 10.1128/Spectrum.00029-21. Online ahead of print.

ABSTRACT

Microbial communities in the airways of persons with CF (pwCF) are variable, may include genera that are not typically associated with CF, and their composition can be difficult to correlate with long-term disease outcomes. Leveraging two large data sets characterizing sputum communities of 167 pwCF and associated metadata, we identified five bacterial community types. These communities explain 24% of the variability in lung function in this cohort, far more than single factors like Simpson diversity, which explains only 4%. Subjects with Pseudomonas-dominated communities tended to be older and have reduced percent predicted FEV1 (ppFEV1) compared to subjects with Streptococcus-dominated communities, consistent with previous findings. To assess the predictive power of these five communities in a longitudinal setting, we used random forests to classify 346 additional samples from 24 subjects observed 8 years on average in a range of clinical states. Subjects with mild disease were more likely to be observed at baseline, that is, not in the context of a pulmonary exacerbation, and community structure in these subjects was more self-similar over time, as measured by Bray-Curtis distance. Interestingly, we found that subjects with mild disease were more likely to remain in a mixed Pseudomonas community, providing some support for the climax-attack model of the CF airway. In contrast, patients with worse outcomes were more likely to show shifts among community types. Our results suggest that bacterial community instability may be a risk factor for lung function decline and indicates the need to understand factors that drive shifts in community composition. IMPORTANCE While much research supports a polymicrobial view of the CF airway, one in which the community is seen as the pathogenic unit, only controlled experiments using model bacterial communities can unravel the mechanistic role played by different communities. This report uses a large data set to identify a small number of communities as a starting point in the development of tractable model systems. We describe a set of five communities that explain 24% of the variability in lung function in our data set, far more than single factors like Simpson diversity, which explained only 4%. In addition, we report that patients with severe disease experienced more shifts among community types, suggesting that bacterial community instability may be a risk factor for lung function decline. Together, these findings provide a proof of principle for selecting bacterial community model systems.

PMID:34232099 | DOI:10.1128/Spectrum.00029-21

Clin Chem. 2021 Jul 6;67(7):1037-1038. doi: 10.1093/clinchem/hvab018.

NO ABSTRACT

PMID:34229341 | DOI:10.1093/clinchem/hvab018

J Cyst Fibros. 2021 Jul 2:S1569-1993(21)01287-X. doi: 10.1016/j.jcf.2021.06.003. Online ahead of print.

ABSTRACT

BACKGROUND: Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10 kb C-to-T splicing mutation in the CFTR gene.

METHODS: We have screened, in FRT cells expressing the 3849+10 kb C-to-T splicing mutation, ~30 2'-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10 kb C-to-T allele.

RESULTS: A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2'-Methoxy Ethyl modification (2'MOE).

CONCLUSION: The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.

PMID:34226157 | DOI:10.1016/j.jcf.2021.06.003

J Heart Lung Transplant. 2021 May 30:S1053-2498(21)02337-8. doi: 10.1016/j.healun.2021.05.016. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic Lung Allograft Dysfunction (CLAD) limits long-term survival following lung transplantation. Colonization of the allograft by Pseudomonas aeruginosa is associated with an increased risk of CLAD and inferior overall survival. Recent experimental data suggests that 'cloaking' antibodies targeting the O-antigen of the P. aeruginosa lipopolysaccharide cell wall (cAbs) attenuate complement-mediated bacteriolysis in suppurative lung disease.

METHODS: In this retrospective cohort analysis of 123 lung transplant recipients, we evaluated the prevalence, risk factors and clinical impact of serum cAbs following transplantation.

RESULTS: cAbs were detected in the sera of 40.7% of lung transplant recipients. Cystic fibrosis and younger age were associated with increased risk of serum cAbs (CF diagnosis, OR 6.62, 95% CI 2.83-15.46, p < .001; age at transplant, OR 0.69, 95% CI 0.59-0.81, p < .001). Serum cAbs and CMV mismatch were both independently associated with increased risk of CLAD (cAb, HR 4.34, 95% CI 1.91-9.83, p < .001; CMV mismatch (D+/R-), HR 5.40, 95% CI 2.36-12.32, p < .001) and all-cause mortality (cAb, HR 2.75, 95% CI 1.27-5.95, p = .010, CMV mismatch, HR 3.53, 95% CI 1.62-7.70, p = .002) in multivariable regression analyses.

CONCLUSIONS: Taken together, these findings suggest a potential role for 'cloaking' antibodies targeting P. aeruginosa LPS O-antigen in the immunopathogenesis of CLAD.

PMID:34226118 | DOI:10.1016/j.healun.2021.05.016

Genet Epidemiol. 2021 Jul 5. doi: 10.1002/gepi.22422. Online ahead of print.

ABSTRACT

The X-chromosome is often excluded from genome-wide association studies because of analytical challenges. Some of the problems, such as the random, skewed, or no X-inactivation model uncertainty, have been investigated. Other considerations have received little to no attention, such as the value in considering nonadditive and gene-sex interaction effects, and the inferential consequence of choosing different baseline alleles (i.e., the reference vs. the alternative allele). Here we propose a unified and flexible regression-based association test for X-chromosomal variants. We provide theoretical justifications for its robustness in the presence of various model uncertainties, as well as for its improved power when compared with the existing approaches under certain scenarios. For completeness, we also revisit the autosomes and show that the proposed framework leads to a more robust approach than the standard method. Finally, we provide supporting evidence by revisiting several published association studies. Supporting Information for this article are available online.

PMID:34224641 | DOI:10.1002/gepi.22422

J Pediatr Gastroenterol Nutr. 2021 Jun 29. doi: 10.1097/MPG.0000000000003218. Online ahead of print.

ABSTRACT

We reviewed INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in 5 (1.2%); 2 had ARP, 3 CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in 4, mild AP in 1. Venous thrombosis occurred in 4, arterial pseudoaneurysm (left gastric artery) in 1. 2 patients with venous thrombosis were treated with anticoagulant, 1 achieved recanalization (splenic vein). In 2 patients who did not receive anticoagulants, 1 re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated.

PMID:34224489 | DOI:10.1097/MPG.0000000000003218

Arch Razi Inst. 2021 Jul;76(2):397-406. doi: 10.22092/ari.2020.128554.1416. Epub 2021 Jul 1.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease with a high rate of morbidity and mortality. Children with CF commonly suffer from recurrent and persistent pulmonary tract infections caused by diverse bacterial pathogens. This study aimed to investigate the prevalence, antimicrobial susceptibility, and biofilm formation of bacterial isolates in pediatric patients with CF. The study population of this cross-sectional study included 8,908 children suspected to have CF by clinical manifestations from March 2015 to August 2017 who were referred to the Tehran Pediatric Central Hospital, Iran. The tests carried out for each participant included screening sweat test, sputum culture, antibiotic susceptibility test using Kirby-Bauer disk diffusion method, and biofilm formation in microtiter plates method. Based onclinical examination and screening sweat test, 183 (2.05 %( out of 8,908 children, were positive for CF. The mean age of children was estimated at 2.93 years, and the majority of them were male (n=103, 56.2%). No gender-specific difference was observed in CF disease in this study (P&amp;gt;0.05). In addition, the results of sputum culture showed that 153 (83.6%) microorganisms (bacteria and fungi) were collected from CF patients. Normal flora was isolated in 30 (16.4%) patients and more than one bacterial species were isolated in 7.2% of patients. The obtained results indicated that Pseudomonas aeruginosa was the most prevalent isolated bacteria followed by Staphylococcus aureus, and Klebsiella pneumoniae. Based on the antibiotic susceptibility test results, P. aeruginosa and piperacillin/tazobactam had the highest (11.7%) and the lowest (2.3%) resistance rate against gentamicin, respectively. However, all K. pneumoniae isolates were resistant to Cefotaxime. Among S. aureus isolates, 83.4% and 16.6% were methicillin-susceptible Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus respectively. Concerning biofilm formation, 76%, 67%, and 72.5% of P. aeruginosa, S. aureus, and K. pneumoniae isolates were biofilm producers, respectively. Based on the study results, P. aeruginosa was the dominant pathogen in pediatric patients with CF from Tehran, Iran, and most of the pathogens were biofilm producers. No severe antibiotic resistance was observed in the isolates; however, the anti-microbial resistance profile should be carefully checked in CF patients on a regular basis.

PMID:34223738 | DOI:10.22092/ari.2020.128554.1416

JAC Antimicrob Resist. 2021 Mar 16;3(1):dlab026. doi: 10.1093/jacamr/dlab026. eCollection 2021 Mar.

ABSTRACT

BACKGROUND: Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide.

OBJECTIVES: In this retrospective study we analysed the 'real-world' TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance.

METHODS: All adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015-17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing.

RESULTS: 91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence.

CONCLUSIONS: Our study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.

PMID:34223100 | PMC:PMC8210303 | DOI:10.1093/jacamr/dlab026

Acta Pharm Sin B. 2021 Jun;11(6):1412-1433. doi: 10.1016/j.apsb.2020.12.003. Epub 2020 Dec 9.

ABSTRACT

Anoctamin 1 (ANO1) or TMEM16A gene encodes a member of Ca2+ activated Cl- channels (CaCCs) that are critical for physiological functions, such as epithelial secretion, smooth muscle contraction and sensory signal transduction. The attraction and interest in ANO1/TMEM16A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases, including asthma, neuropathic pain, hypertension and cancer. However, the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target. This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools, hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.

PMID:34221860 | PMC:PMC8245819 | DOI:10.1016/j.apsb.2020.12.003

Cureus. 2021 Jun 26;13(6):e15948. doi: 10.7759/cureus.15948.

ABSTRACT

Background and purpose Neutrophil elastase (NE) has been implicated in the pathogenesis of airway inflammation in cystic fibrosis (CF) patients and it impairs defenses against Pseudomonas aeruginosa (PA) infection or colonization. Sputum NE may act as a biomarker of neutrophilic inflammation in CF patients. This study aimed to determine sputum and plasma total NE levels in clinically stable adult CF patients and control subjects, and their correlation to PA colonization and lung functions. Methods This is a cross-sectional study. Total NE was measured on spontaneously expectorated sputum and plasma obtained from 21 CF patients, aged 18-40 years, during routine visits to the adult CF clinic. This was compared to plasma obtained from 22 matching healthy controls. The levels of NE were measured by the magnetic bead-based multiplex assay. Results Sputum and plasma NE levels had a significant positive correlation (Pearson r=0.533, P=0.013) with PA colonization. Sixteen CF patients (76.2%) were chronically colonized with PA. Both median sputum and plasma NE were found to be higher in CF patients with PA as compared with non-PA patients, even though this difference was statistically insignificant. Sputum and plasma NE levels did not correlate with the percentage predicted forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and FEV1/FVC and no association with PA. Conclusion The findings suggest that clinically stable adult CF patients colonized with PA may have higher NE levels in both plasma and sputum as compared to non-PA CF patients and probably total NE does not influence lung functions.

PMID:34221778 | PMC:PMC8238017 | DOI:10.7759/cureus.15948